Mental retardation syndromes and age-related cognitive diseases are disorders that degrade the quality of life of afflicted individuals and apply a serious toll on society in general. While the causes of some of these conditions are known, the basis for cognitive impairment is generally not understood. Current theories suggest that many forms of impairment arise from aberrant spine morphology and synaptic plasticity and that facilitation of these processes will enhance cognitive function. The endogenous neurotrophin, brain derived neurotrophic factor (BDNF) modulates spine shape and facilitates synaptic plasticity in adult brain. These and other results suggest that BDNF may be critical for structural changes that underlie functional synaptic plasticity. The proposed research will investigate the role of endogenous BDNF signaling via its TrkB receptor in activity-induced remodeling of the dendritic spine actin cytoskeleton and synapse size in association with long term potentiation (LTP), a form of plasticity thought to underlie learning. Studies will use adult rat hippocampal slices to test the hypothesis that theta burst afferent stimulation (TBS) elicits BDNF-dependent activation of spine TrkB which, in turn, signals through the actin regulatory protein cofilin to increase spine F-actin levels and the size of synapses involved in LTP. Aim 1 will test if TBS activates TrkB in spines engaged in LTP: immunocytochemistry and restorative deconvolution microscopy will be used to test if TBS activates TrkB (i.e., increases Trk autophosphorylation) in the lamina of afferent stimulation. Aim 2 will use similar techniques to test if TBS effects on phospno-Trk depend on both extracellular TrkB ligands and signaling from integrins (the latter known to modulate receptor tyrosine kinase activities in other systems). Aim 3 will test the hypothesis that TBS-induced Trk signaling contributes to activation of an actin signaling cascade and to an increase in synapse size. The separate studies under Aim 3 will test (3A) if TBS increases the size of PSD95-immunoreactive synapses associated with phospho- Trk, (3B) if TBS-induced increases phospho-Trk are upstream to changes in the spine filamentous (F)-actin (i.e. are not blocked by latrunculin A which prevents actin filament assembly) and (3C) if signaling through TrkB is needed for TBS-induced increases in spine phospho-PAK, spine phospho-cofilin, and increases in synapse size thought to underlie stable LTP. This project will serve as the first direct analysis of BDNF-to actin signaling involved in adult synaptic plasticity. Understanding this process may provide insight into a shared basis of learning impairments associated with several neuro-cognitive diseases and identify therapeutic targets for enhancing function with these disorders.